Porphyromonas gingivalis is a leading pathogen in chronic periodontitis, a disease process involving progressive destruction of tissues that support the teeth. Recently, the organism has been reported to produce a unique bacterial enzyme, P. gingivalis peptidylarginine deiminase (PPAD), which has the ability to convert arginine residues in proteins to citrulline. Protein citrullination alters protein structure and function, hence, PPA may be involved in dysregulation of the host's signaling network for immune evasion. Further, accumulating evidence has revealed the role of autoimmunity against citrullinated proteins in the development of rheumatoid arthritis (RA). As inflammatory conditions in the lungs of cigarette smokers contributes to the breakdown of immune tolerance to citrullinated epitopes, chronic exposure to citrullinated proteins at periodontitis sites may also predispose susceptible individuals to the development of autoantibodies and initiation of RA. Thus, PPAD may represent the mechanistic link between periodontitis and rheumatoid arthritis - diseases that are known to be significantly associated to each other at the epidemiological level. We hypothesize that citrullination of bacterial and host proteins in periodontal/gingival tissues by PPAD, within the chronic inflammatory environment and immune system stimulation by bacteria- derived danger signals, leads to the initial break of immune tolerance to citrullinated proteins and peptides. In addition PPAD may manipulate immune responses in inflamed periodontal tissues by modifying important effector molecules of the innate immunity, including C3a and C5a anaphylatoxins and bradykinin. Biological activity of these peptides depends on the C-terminal arginine, which is also a preferential target for PPAD. Hence, this research proposal will investigate the important and innovative concept that PPAD as a virulence factor of P. gingivalis and mechanistic link between periodontitis and RA with the following specific aims: (i) in vivo and ex vivo examination of PPAD's role in the pathogenesis of RA; (ii) functional and structural studies of various forms of PPAD; and (iii) investigate the immunomodulatory effect of PPAD that is relevant to the pathogenesis of periodontal disease. Thus, the proposed research will illuminate the PPAD's contribution to chronic inflammation driven by P. gingivalis infection and shed light on the possible link between periodontal disease and rheumatoid arthritis. This knowledge will create new perspectives in the treatment of periodontitis and prevention of rheumatoid arthritis in susceptible individuals.